tbuckley/cabot-search huggingface dataset:
Characterizing the immune phenotype of FGFR3 mutated upper tract urothelial carcinoma (UTUC) using single-cell (sc)RNA-sequencing (seq).
Authors: Andrew B Katims, Fengshen Kuo, Peter Reisz, Andrew Tracey, Jasmine Thomas, Wesley Yip, Taha Merghoub, Bernard H. Bochner, Eugene J. Pietzak, David B. Solit, A. Ari Hakimi, Kwanghee Kim, Jonathan Coleman
Journal: Journal of Clinical Oncology (2023)

558 Background: Fibroblast growth factor 3 (FGFR3) is the most common mutation in UTUC and is altered in approximately 75% of tumors. Tumors harboring FGFR3 mutations (FGFR3-M) have a T-cell impaired tumor microenvironment (TME) which may explain the incomplete response to immune checkpoint blockade. We performed scRNA-seq on 8 untreated tumors to further characterize the T-cell immune phenotype of FGFR3-M tumors. Methods: scRNA-seq (10x Genomics platform) was performed on 8 UTUC tissue specimens from 8 different patients who had not received treatment (chemotherapy or immunotherapy) using an established institutional process. We also performed targeted gene sequencing (MSK-IMPACT) on all samples to identify mutational calls. We assessed the phenotype of defined cell clusters and the immune composition of each sample according to known marker gene expression as well as SingleR prediction. We then performed the gene set enrichment analysis over the differentially expressed genes with the Gene Ontology Biologic Process (GO:BP) to identify unique biologic processes and possible functional state of each immune cluster. Results: Among the 8 samples, 4 (50%) had altered FGFR3 (Table). We identified 19 immune cell clusters (8 T-cell clusters) with unique biologic function. Within the CD4 compartment, FGFR3-M was enriched with exhausted/active CD4 cells characterized with Th17 cell differentiation/immune regulatory function (cluster 4) and yet with lower frequency of naive-like CD4 cells possessing alpha-beta T cell activation functions and lower T-cell receptor (TCR) signaling (cluster 2). Regulatory T cells (cluster 5) were less frequently found in FGFR3-M tumors compared to their wild-type counterpart. In the CD8 compartment, FGFR3-M tumors had higher infiltration specifically in cluster 3 which corresponds to a naïve state with lower exhausted/active markers, lower cytotoxic activity, leukocyte apoptotic process, and alpha-beta T cell differentiation regulation. There was also a lower proportion among cluster 9, a mixture of NK and CD8 cytotoxic cells, which is characterized with response to interleukin (IL)-1, tumor necrosis factor (TNF), and NK cell chemotaxis. Additionally, this cluster had high cytotoxic activity and lower exhausted/active markers. Conclusions: FGFR3 mutated patients have a T-cell phenotype with more active/exhausted Th17-like CD4, lower Treg, and more CD8/cytotoxic cells in naïve state with lower response to IL-1 and TNF. scRNA-seq revealed enrichment of different functional states among T-cell compartments which may lead to improved therapeutic decision making in the future. [Table: see text]
Prognostic value of integrated liquid biopsies in patients (pts) with metastatic urothelial cancer (mUC).
Authors: Charlotte Stahlfeld, Hamid Emamekhoo, Katherine Kaufmann, Petros Grivas, Moshe Chaim Ornstein, Iris Yeong- Fung Sheng, Caroline Burkey, Jamie Sperger, Rory M. Bade, Jennifer L. Schehr, Amy K Taylor, Yue Shi, Shuang Zhao, Joshua Michael Lang
Journal: Journal of Clinical Oncology (2023)

547 Background: Despite recent therapeutic advancements for patients with mUC, including checkpoint inhibitors (CPIs), anti-FGFR and antibody-drug conjugates (ADCs), biomarker data to predict therapeutic response and identify mechanisms of resistance remain limited. Ongoing randomized clinical trials evaluating the combination of CPIs and ADCs in these pts underscore the need to develop biomarkers to better understand who might best respond to these therapies. Here, we employ a liquid biopsy approach to molecularly characterize circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), including those isolated with Trop-2, the target of the novel drug Sacituzumab Govitecan and Datopotamab Deruxtecan. Methods: 104 blood samples serially collected from pts being treated for mUC were used for CTC collection using anti-EpCAM and Trop-2 antibodies in parallel. CTCs were isolated and stained for immune markers PD-L1 and HLA I using the VERSA (Versatile Exclusion-based Rare Sample Analysis) platform. Plasma was isolated for paired analysis of CTC and ctDNA content. CTCs were analyzed for enumeration and single-cell protein analysis. Overall survival (OS) was defined from time of sample collection, and survival analyses were performed using the Kaplan-Meier method. Results: We observed significantly shorter OS in pts with higher CTC burden (≥ 20 CTCs/7.5 mL blood) in samples captured with either EpCAM (median 34.1 vs 3.1 mo, P &lt; 0.01) or Trop-2 (median 34.1 vs 6.2 months, P &lt; 0.01). Furthermore, EpCAM and Trop-2 CTC burdens were higher at progression timepoints relative to responding or stable timepoints, when stratified according to treatment modality (table). Inter and intra-patient heterogeneous PD-L1 and HLA I expression and co-expression was observed on CTCs although no significant differences were seen globally between EpCAM and Trop-2 CTCs. In a cohort of pts treated with CPIs, we observed dynamic phenotypic changes in the ratio of HLA:PD-L1 that differed between EpCAM and Trop-2 CTCs. ctDNA analysis identified concordant increases in tumor fraction and acquired genomic mutations. When examined longitudinally across individual pts, these findings in tandem with changes in enumeration, suggest the emergence of different CTC subpopulations that may serve as biomarkers of resistance. Conclusions: We identify the prognostic significance of CTC enumeration with parallel EpCAM and Trop-2 CTC isolation and demonstrate the utility of a liquid biopsy assay that can detect pharmacodynamic changes in CTC burden and immune marker expression throughout the course of treatment. [Table: see text]
5-Year result of single-institute cohort study in single-fraction HDR monotherapy for localised prostate cancer.
Authors: Imtiaz Ahmed, Khin Sandar Tun, Sharon Shibuthomas, Alex Cain, Sadia Mahar, Nicola Yoganayagam, Abby Cyriac, Mahbuba Choudhury, Daben Dawam
Journal: Journal of Clinical Oncology (2023)

362 Background: The aim if this single institute UK-based study was to look at 3-year and 5-year bRFS and toxicity profiles. Methods: It is a prospective data study with a total number of 174 patients who were treated with single-fraction HDR monotherapy between July 2014 and February 2017. Biochemical recurrence is defined using Phoenix criteria. Results: The median age was 67.5 years with the median presenting PSA of 8. Majority of patients were lower risk group with 55% for combined low and favourable intermediate risks. 81 patients had Gleason score 6(3+3) and 77 patients had GS 7(3+4). Total hormone duration was 8 months and median duration of hormone prior to HDR monotherapy was 4 months. Overall bRFS at 3 years was 96% and 5 years was 88%. 5-year bRFS as per risk stratification was 100% in low risk, 92% in favourable intermediate risk, 83% in unfavourable intermediate risk and 79% in high-risk groups. This study had better 5-year overall bRFS compared to published data in single fraction HDR monotherapy (88% vs 73.5%, p value 0.001) (Morton et al., 2020). Despite inferior 5-year overall bRFS in compared to 2-fractionated HDR monotherapy (88% vs 95%) (p value 0.001), no difference in 5-year bRFS noted in low and favourable intermediate risk groups (100% vs 100% and 92% vs 93% respectively) (Morton et al., 2020). Two-thirds (71%) of biochemically recurred patients found to have local recurrence disease. The median time of biochemical recurrence was 47 months. Higher risk groups had higher 5-year biochemical recurrence risk. Acute and late toxicity profiles were minimum with acute G2 GU toxicity (2%) and GI toxicity (1%); late G2 GU toxicity (2%) and GI toxicity (0%) with no G3, G4 GU or GI toxicities. Conclusions: This prospective study had shown better overall 5-year bRFS especially in low and favourable intermediate risk groups with minimal toxicities. Therefore, single-fraction HDR monotherapy could be considered for elderly or patients with significant co-morbidities who are more suitable for single treatment rather than 2 fractions in these risk groups. Further randomised multicentre studies in these risk groups are suggested.
Pathologic response with neoadjuvant chemotherapy, immunotherapy, and chemo-immunotherapy for muscle-invasive bladder cancer (MIBC): A systematic review and meta-analysis.
Authors: Ahsan Ayaz, Syed Arsalan Ahmed Naqvi, Nikita Tripathi, Hafsah Ijaz, Sajid Ahmad Mir, Parminder Singh, Syed A. Hussain, Guru P. Sonpavde, Bradley Alexander McGregor, Alan Haruo Bryce, Irbaz Bin Riaz, Praful Ravi
Journal: Journal of Clinical Oncology (2023)

531 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) is established in the management of MIBC. Pathologic complete response (pCR, ypT0N0) and downstaging (&lt;ypT2N0) are associated with long term survival in patients with MIBC. Several trials have evaluated neoadjuvant immunotherapy (NAI) and chemoimmunotherapy (NACI) for MIBC. We aimed to conduct a meta-analysis of available trials to compare the incidence of pathological response with NAC, NAI and NACI in MIBC patients undergoing radical cystectomy. Methods: Phase II/III clinical trials assessing neoadjuvant systemic therapies (NAC, NAI, or NACI) in patients with MIBC undergoing radical cystectomy were identified through a systematic search of MEDLINE and EMBASE. Outcomes of interest included pCR and pathological downstaging. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled incidence of events using the Freeman-Tukey transformation. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: Of the 5357 records initially identified, 28 trials with a total of 2138 patients were considered eligible for inclusion. Neoadjuvant chemotherapy was assessed in 15 trials (1535 patients), NAI in 5 (288 patients), and NACI in 8 (315 patients). The pooled incidence of patients experiencing a pCR was 30.91% (95% CI: 26.54%-35.45%) with NAC, 30.92% (23.22%-39.14%) with NAI, and 42.25% (36.6%-48.0%) with NACI. The difference in pCR among these therapies was statistically significant (p &lt;0.05). Similarly, the pooled incidence of achieving pathological downstaging was 40.91% (34.26%-47.72%) with NAC, 38.84% (26.73%-51.64%) with NAI, and 62.88% (57.22%-68.39%) with NACI. Consistently, there was statistically significant effect modification by the choice of neoadjuvant systemic therapy (p &lt;0.01). The results were consistent across different clinically important subgroups (Table). Conclusions: NACI may achieve better pCR and pathological downstaging than NAC and NAI alone in MIBC patients which may potentially be associated with long-term survival. Definitive data from phase III trials are pending. [Table: see text]
Patient perceptions of benefits and risks of adjuvant therapy in renal cell carcinoma.
Authors: Dena Battle, Pavlos Msaouel, Sumanta Monty Pal, Ulka N. Vaishampayan, Michael D. Staehler
Journal: Journal of Clinical Oncology (2023)

663 Background: Adjuvant treatment with the immune checkpoint inhibitor (CPI) pembrolizumab and the tyrosine kinase inhibitor (TKI) sunitinib are currently standard of care options for patients with high-risk localized renal cell carcinoma (RCC). However, treatment decisions need to be based on anticipated benefit, toxicity risk, and patient goals and values, particularly since multiple trials testing CPIs and TKIs in the adjuvant setting did not meet their primary endpoints. To improve patient selection and communication, we sought to assess how patients perceive the benefits and risks of adjuvant therapy. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure), with multidisciplinary representation from urologic surgeons, medical oncologists and patient advocates. The survey was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Out of 1,062 participants 639 patients self-identified with localized RCC and 223 patients had stage 3 RCC at initial diagnosis. 113 patients were offered adjuvant therapy by their doctor, 74 patients reported being treated with or having received treatment with adjuvant therapy (18% treated with TKI, 82% with CPI). Results: When asked to assess risk of recurrence, patients with stage 3 disease assessed their average personal risk to be 47%, 10% higher than what they reported their doctor assessed risk to be (37%). When asked to identify the most important factors related to adjuvant decision making, patients ranked risk of dying from cancer (76%) over severity of possible side effects (43%), chance of having side effects (35%), time required for treatment (24%), and cost of treatment (7%). 49% of patients offered adjuvant therapy believe that treatment reduces the risk of recurrent disease by more than 30% and 25% believe it reduces risk by more than 50%. Among patients receiving or having received adjuvant therapy, 46% completed adjuvant therapy, 17% stopped early due to side effects and 14% recurred while on therapy. Side effects were asymptomatic or mild in 38%, moderate without invasive intervention or hospitalization in 48% severe, requiring hospitalization in 8% and life-threatening in 7%. 22% of patients were told that their side effects would be life-long. Conclusions: Patients with high-risk localized disease estimate their recurrence risk to be higher than what their doctors assess their risk to be. When weighing decisions about adjuvant therapy, patients rank risk of dying from cancer over risks related to toxicity. An overestimation of benefits of adjuvant therapy is noted with one quarter of patients believing that adjuvant therapy will reduce their risk of recurrence by 50 percent or more. The findings highlight the importance of effective communication between patients and providers regarding the risks and benefits of adjuvant therapy to promote an informed and shared decision.
Contemporary use of wearable activity monitors in prostate cancer survivors: A scoping review.
Authors: Brandon Noorvash, Carolina Raines, Edwin Melencio Posadas, Howard M. Sandler, Stephen J. Freedland, Gillian Gresham
Journal: Journal of Clinical Oncology (2023)

127 Background: Remote monitoring of daily activity using wearable activity monitors (“wearables”) (e.g., Fitbits) provides an unintrusive method to obtain continuous, objective physical activity (PA) and sleep data outside the clinical setting. Despite their potential for improving PA assessment for cancer survivors, there is currently limited information on how wearables are being used in PCa survivors. Thus, we reviewed the literature to understand how wearables are being integrated into research and interventional studies conducted in PCa survivors. Methods: We searched PubMed, CENTRAL, and Clinicaltrials.gov for randomized controlled trials (RCTs) and observational studies that involve commercially available wearables in PCa survivors, published between 2012 and 2022. Upon screening and full-text review by two independent reviewers, data were extracted from eligible studies, including study and patient characteristics, details on study interventions and outcomes, and purpose of device use. Baseline PA data were abstracted from articles with available quantitative data, including step counts, time spent in moderate-to-vigorous physical activity (MVPA), and sleep duration, and included in a quantitative analysis. Results: Eighty studies were screened and 17 studies met eligibility criteria and were included in this review (8 RCTs; 9 observational), with a total sample size of 1,148 PCa survivors (median age 66 years, range 39-84). Wearables used included: Fitbit: (47%), pedometer (18%), smartphone (6%), Jawbone (6%), and heart rate monitor (6%). Most studies (71%) involved individual or group-based exercise interventions that were either gym-based supervised by an exercise physiologist or home-based (online web-based delivery or written recommendations), as well as remotely delivered behavioral interventions. One study compared objective (actigraphy) and subjective sleep quality measures and one was a validation study comparing Fitbit to the ActiGraph accelerometer. Study durations ranged from 1-48 weeks with median reported adherence to wearing the device of 79.5% (range 63-100%). PA data, as measured with wearables, were available in 13 studies and summarized. Conclusions: Wearables are increasingly being used to assess daily activity and monitor adherence to exercise interventions in PCa survivors. Findings suggest wearables are feasible for use in this population with high levels of adherence. Wearables can provide added value to PA and functional assessment, although more research is needed to understand how wearables can be integrated into routine patient care or used as means to track or deliver tailored interventions for PCa survivors. [Table: see text]
Predicting perioperative complications for partial versus radical nephrectomy in T1b-T2 renal cell carcinoma.
Authors: Yash Shah, Kerith Ruoyao Wang, Rishabh Kumar Simhal, Hanan Goldberg, James Ryan Mark, Mihir S Shah, Leonard G. Gomella, Costas D. Lallas, Thenappan Chandrasekar
Journal: Journal of Clinical Oncology (2023)

737 Background: The standard of care for larger localized RCC lesions is radical (RN) or partial (PN) nephrectomy. RN is increasingly utilized to maximize oncologic benefit in complex tumors. Although PN is a more technically complex procedure, its nephron-sparing nature confers lasting renal and cardiovascular benefits. We utilized the National Surgical Quality Improvement Program (NSQIP) database to elucidate predictors of perioperative morbidity in T1b-T2 RCC patients. Methods: Using the NSQIP Nephrectomy-Targeted PUF, 2,094 patients undergoing nephrectomy between 2019-2020 for localized T1b-T2 RCC were identified. Variables of interest included surgical procedure and approach, tumor stage, demographics, pre-operative laboratory values, comorbidities, infection and venothromboembolism (VTE) prophylaxis techniques, peri-operative complications, operative time, length of hospital stay, 30-day reoperations, and 30-day readmissions. Chi square test was used to analyze univariate associations between certain comorbidities and complications. Multivariate regression analysis was utilized to compare complication rates between PN and RN after adjusting for baseline characteristics and surgical approach. p&lt;0.05 was considered statistically significant. Results: 816 patients received PN while 1,278 received RN. PN patients had an increase in the following events: 30-day readmissions (7.0% vs. 4.7%, p=0.026), major bleeds (9.19% vs. 5.56%, p=0.001), renal failure requiring dialysis (1.23% vs. 0.31%, p=0.013), and urine leak or ureteric fistulae (1.10% vs. 0.31%, p=0.025). Open surgery was associated with increased VTE, renal failure, bleeds, urine leaks or ureteric fistulae, readmissions, and reoperations. Multivariate analysis revealed that PN remained predictive of all four aforementioned events, although further adjustment for robotic approach led to a loss of significance for renal failure and ureteric fistulae. Additional patient-specific predictors of relevant complications across procedure type included bleeding disorder and dialysis for bleeds, and renal failure, steroid use, and COPD for readmissions. Conclusions: This is the first study to evaluate the new NSQIP Nephrectomy-Targeted PUF. This population-based cohort provides unique insights into nephrectomy for pT1b-T2 localized RCC. We demonstrate significant associations between PN and specific complications, modulated by particular comorbidities, although both PN and RN were exceedingly safe. This analysis supports the development of novel risk stratification tools which account for specific patient comorbidities in predicting near term risk. Improved understanding of case-specific determinants of morbidity following PN or RN may facilitate shared decision making in localized RCC management.
Distinct genomic features and evolutionary relationships between concurrent intraductal carcinoma and adenocarcinoma of the prostate.
Authors: Sha Zhu, Jinge Zhao, Ling Nie, Mengni Zhang, Linmao Zheng, Nanwei Xu, Pengfei Shen, Ni Chen, Hao Zeng, Guangxi Sun
Journal: Journal of Clinical Oncology (2023)

215 Background: Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally co-exists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared to concomitant adenocarcinoma. Till now, the genomic characteristics of IDC-P remain largely unknown. Methods: To explore the genomic features and evolutionary relationships between concurrent IDC-P and PAC, we isolated IDC-P, concurrent invasive high-grade PAC lesions, and adjuvant normal prostate tissues from 22 radical prostatectomy specimens. Whole-exome, RNA, and DNA-methylation sequencing were performed on the acquired tumoral and normal samples. The biological characteristics of IDC-P and concurrent PAC were compared at different molecular levels. Results: Three evolutionary patterns between concurrent IDC-P and PAC were identified. Tumors with clonally distant and early divergent evolutionary patterns showed higher genomic and pathological heterogeneities between concurrent IDC-P and PAC than those with the late-divergent pattern. Compared to co-existing PAC, increased adverse prognosis-associated genes were overexpressed in IDC-P. Besides, IDC-P was similar to Gleason pattern 5 PAC on the transcriptome profile. Survival analysis based on an independent cohort supported IDC-P resembled Gleason pattern 5 tumors. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation-associated master regulators and genes involved in intratumoral androgen biosynthesis. Conclusions: Our findings provide a molecular groundwork for the aggressive behavior of IDC-P and contribute to developing potential therapies for tumors with IDC-P.